This invention relates to compounds which bind to histamine H3 receptors, and to methods of making such compounds.
Histamine is well known as a mediator in certain hypersensitive reactions of the body, such as allergic rashes, hayfever and asthma. These conditions are now commonly treated with potent antagonists of histamine, so-called xe2x80x9cantihistaminesxe2x80x9d.
In the 1940s, it was noted that some physiological effects of histamine, such as increased gastric acid secretion and cardiac stimulation, were not blocked by the antihistamines which were then available. This led to the proposal that histamine receptors exist in at least two distinct types, referred to as H1 and H2 receptors. Subsequently, H2 antagonists (such as cimetidine, ranitidine and famotidine) were identified, and they have become important in the treatment of gastric ulcers.
In the early 1980s, it was established that histamine also has a role as a neurotransmitter in the central nervous system. Arrang et al., Nature 302, 832 to 837 (1983), proposed the existence of a third histamine receptor subtype (H3) located presynaptically on histaminergic nerve endings. Arrang et al. postulated that the H3 receptor is involved in inhibiting the synthesis and release of histamine in a negative feedback mechanism. The existence of the H3 receptor was subsequently confirmed by the development of selective H3 agonists and antagonists (Arrang et al., Nature 327, 117 to 123 (1987)). The H3 receptor has subsequently been shown to regulate the release of other neurotransmitters both in the central nervous system and in peripheral organs, in particular in the lungs and GI tract. In addition, H3 receptors are reported to regulate the release of histamine from mast cells and enterochromaffin-like cells.
A need exists for potent and selective H3 ligands (both agonists and antagonists) as tools in the study of the role of histamine as a neurotransmitter, and in its roles as a neuro-, endo- and paracrine hormone. It has also been anticipated that H3 ligands will have therapeutic utility for a number of indications including use as sedatives, sleep regulators, anticonvulsants, regulators of hypothalamo-hypophyseal secretion, antidepressants and modulators of cerebral circulation, and in the treatment of asthma and irritable bowel syndrome.
A number of imidazole derivatives have been proposed in the patent literature as H3 ligands. Representative are the disclosures of EP-A-0197840, EP-A-0214058, EP-A-0458661, EP-A-0494010, EP-A-0531219, WO91/17146, WO92/15567, WO93/01812, WO93/12093, WO93/12107, WO93/12108, WO93/14070, WO93/20061, WO94/17058, WO95/06037, WO95/11894, WO95/14007, U.S. Pat. Nos. 4,988,689 and 5,217,986.
According to the present invention, there is provided a compound of the formula 
wherein
R1 is selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, carboxy, carboxy(C1 to C6)alkyl, formyl, C1 to C6 alkylcarbonyl, C1 to C6 alkylcarbonylalkoxy, nitro, trihalomethyl, hydroxy, amino, C1 to C6 alkylamino, di(C1 to C6 alkyl)amnino, aryl, C1 to C6 alkylaryl, halo, sulfamoyl and cyano;
R2 is C1 to C20 hydrocarbylene, in which one or more hydrogen atoms may be replaced by halogen atoms and up to 6 carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R2 does not contain a xe2x80x94Oxe2x80x94Oxe2x80x94 group, and provided also that the atom in R2 which is linked to the xe2x80x94SO2xe2x80x94 moiety is a carbon atom;
R3 is hydrogen or C1 to C15 hydrocarbyl, in which one or more hydrogen atoms may be replaced by halogen atoms and up to 3 carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R3 does not contain a xe2x80x94Oxe2x80x94Oxe2x80x94 group;
X is a bond or xe2x80x94NR4xe2x80x94, wherein R4 is hydrogen or non-aromatic C1 to C5 hydrocarbyl (in which one or more hydrogen atoms may be replaced by halogen atoms and up to 2 carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R4 does not contain a xe2x80x94Oxe2x80x94Oxe2x80x94 group), aryl(C1 to C3)alkyl or R4 represents a bond to R2; and
a is from 0 to 2 (preferably 0),
and pharmaceutically acceptable salts thereof.
R2 is preferably C1 to C15 hydrocarbylene, in which one or more hydrogen atoms may be replaced by halogen atoms and up to 4 carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R2 does not contain a xe2x80x94Oxe2x80x94Oxe2x80x94 group. More preferably, R2 is C1 to C8 alkylene or alkenylene, optionally substituted by a hydroxyl group or an oxo group.
R3 is preferably hydrogen, cycloalkyl(C1 to C3)alkyl or aryl(C1 to C3)alkyl. More preferably, R3 is cyclohexyl(C1 to C3)alkyl, adamantyl(C1 to C3)alkyl, or phenyl(C1 to C3)alkyl in which the phenyl group is optionally substituted by halo or methyl.
R4 is preferably hydrogen or C1 to C5 alkyl. When R4 represents a bond to R2, it preferably forms a five- or six-membered ring, which may be fused to a ring system within R2. For example, the moiety xe2x80x94R2xe2x80x94SO2xe2x80x94NR4xe2x80x94 may be an isothiazole dioxide group fused to six-membered carbocyclic ring. In the embodiment of Example 41 below, the moiety xe2x80x94R2xe2x80x94SO2xe2x80x94NR4xe2x80x94 is a 2,3,3a,4,5,7a-hexahydro-benzo[d]isothiazole 1,1-dioxide group.
The invention also comprehends derivative compounds (xe2x80x9cpro-drugsxe2x80x9d) which are degraded in vivo to yield the species of formula (I). Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded. Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of pro-drugs may be found in Stella, V. J. et al., xe2x80x9cProdrugsxe2x80x9d, Drug Delivery Systems, pp. 112-176 (1985), and Drugs, 29, pp.455-473 (1985).
Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (I) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form xe2x80x94COOR5, wherein R5 is C1 to C5 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following: 
Amidated acid groups include groups of the formula xe2x80x94CONR6R7, wherein R6 is H, C1 to C5 alky, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R7 is xe2x80x94OH or one of the groups just recited for R6.
Compounds of formula (I) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution.
Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, and zinc, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, benzathine, diolamine, olamine, procaine and tromethamine.
Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.
The compounds of the invention may exist in various enantiomeric, diastereomeric and tautomeric forms. It will be understood that the invention comprehends the different enantiomers, diastereomers and tautomers in isolation from each other, as well as mixtures of enantiomers, diastereomers and tautomers.
The term xe2x80x9chydrocarbylxe2x80x9d, as used herein, refers to monovalent groups consisting of carbon and hydrogen. Hydrocarbyl groups thus include alkyl, alkenyl, and alkynyl groups (in both straight and branched chain forms), cycloalkyl (including polycycloalkyl), cycloalkenyl, and aryl groups, and combinations of the foregoing, such as alkylaryl, alkenylaryl, alkynylaryl, cycloalkylaryl, and cycloalkenylaryl groups. The term xe2x80x9chydrocarbylenexe2x80x9d refers to corresponding divalent groups, the two free valencies being on separate atoms.
When reference is made herein to a carbon atom of a hydrocarbyl group being replaced by O, S or N, it will be understood that what is meant is that a xe2x80x94CH2xe2x80x94 group is replaced by xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, or that 
is replaced by 
A xe2x80x9ccarbocyclicxe2x80x9d group, as the term is used herein, comprises one or more closed chains or rings, which consist entirely of carbon atoms, and which may be substituted. Included in such groups are alicyclic groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl), groups containing both alkyl and cycloalkyl moieties (such as adamantanemethyl), and aromatic groups (such as phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl).
The term xe2x80x9carylxe2x80x9d is used herein to refer to aromatic carbocyclic groups, including those mentioned above, which may be substituted.
A xe2x80x9cheterocyclicxe2x80x9d group comprises one or more closed chains or rings which have at least one atom other than carbon in the closed chain or ring, and which may be substituted. Examples include benzimidazolyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl.
When reference is made herein to a substituted carbocyclic group (such as substituted phenyl) or a substituted heterocyclic group, the substituents are preferably from 1 to 3 in number and selected from C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, carboxy, carboxy(C1 to C6)alkyl, formyl, C1 to C6 alkylcarbonyl, C1 to C6 alkylcarbonylalkoxy, nitro, trihalomethyl, hydroxy, amino, C1 to C6 alkylamino, di(C1 to C6 alkyl)amino, halo, sulfamoyl and cyano.
The term xe2x80x9chalogenxe2x80x9d, as used herein, refers to any of fluorine, chlorine, bromine and iodine.
We have found that a number of compounds in the prior art have shown a significant discrepancy in their activity as measured by two ileum based assays which are described below. We would interpret discrepancies between the functional and binding assays of greater than about 0.5 log units as significant. Analysis of data obtained in these particular functional and radioligand binding assays and also in other related bioassays suggests that the discrepancy may be connected, at least in part, with residual efficacy inherent in these structures. In practice, this means that these particular compounds may act as agonists, at least in some tissues.
Surprisingly, we have found that the compounds disclosed herein do not show a significant discrepancy in the two assays. Thus, these compounds may be considered to have minimal potential to express agonist action, and would be expected to behave as antagonists or, at constitutively-active receptors, as inverse agonists. In one aspect, therefore, the present invention provides the use of these compounds as histamine antagonists or inverse agonists, and in the manufacture of medicaments for this purpose.
Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer""s solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
Effective doses of the compounds of the present invention may be ascertained by conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including the severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 xcexcg/kg and 50 mg/kg, especially between 10 xcexcg/kg and 10 mg/kg, e.g. between 100 xcexcg/kg and 2 mg/kg.
Compounds according to Formula I in which X is xe2x80x94NHxe2x80x94 can conveniently be prepared via the key intermediates 2a and 2b (FIG. 1), using the existing methods of Tozer5 and Thompson6. In FIG. 1, Z is H or a Boc group or other suitable migrating group, Z1 is a protecting group, Z2 is H or a further protecting group, and R2a is C1 to C18 hydrocarbylene. Compound 2b may also be obtained from compound 2a when Z is other than H by treatment with a base such as caesium carbonate. Compound 2a may be deprotected e.g. with trifluoroacetic acid to yield a compound of the formula 
If compound 2b is deprotected under appropriate conditions, the result is a compound of the formula 
If compound 2b is reduced (e.g. by hydrogenation over a palladium/charcoal catalyst), and then deprotected, the result is a compound of formula 
If compound 2b is allowed to react with an amine R8R9NH and deprotected, then a compound of the formula 
is produced. This route is shown in FIG. 2. R8 and R9 are independently H, lower (eg C1 to C5) alkyl, or are linked to each other to form an N-containing ring.
Compound (1) in FIG. 1 may be prepared by conventional methods, such as by reaction of mesyl chloride with a compound of formula R3NH2 in the presence of a base such as triethylamine. If Z is other than H, the methanesulfonamide R3NHSO2Me may be treated with suitable reagents for protection (e.g. Boc2O, catalytic DMAP) to give compound (1).
Compounds of Formula I in which X is xe2x80x94NHxe2x80x94 may also be prepared by reacting a compound of formula 
with a compound of formula R3NH2 in the presence of a base.
When X is xe2x80x94NR4xe2x80x94 and R4 is other than H, the R4 group may be introduced by chemistry on late-stage protected intermediates well known to those skilled in the art.
Compounds of Formula I in which X represents a bond may be obtained by reacting a suitably protected compound of formula 
(wherein Y represents a leaving group such as bromide) with a compound of formula R3SH, followed by oxidation of the resulting thioether to yield the desired sulfone. Protection of the imidazole ring may conveniently be by means of the procedure described in Example 23 below. Oxidation of the thioether can be achieved using a suitable oxidising agent such as Oxone(copyright).
Compounds of Formula I in which X represents xe2x80x94NR4xe2x80x94 and R4 represents a bond to R2 may be prepared by methods analogous to that illustrated in FIG. 3. Compound (3) in FIG. 3 is a suitably N-protected derivative of the compound of Formula II above in which R2a is xe2x80x94CHxe2x95x90CHxe2x80x94. This compound is treated with sodium hydride, and then with allyl bromide, to form the N-allyl derivative (4). Ring closure is then effected by heating under pressure in a suitable dry solvent such as toluene.